CN1303271A - Preparations for application of anti-inflammatory, especially antiseptic agents and/or agents promoting healing of wounds, to lower respiratory tract - Google Patents

Preparations for application of anti-inflammatory, especially antiseptic agents and/or agents promoting healing of wounds, to lower respiratory tract Download PDF

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CN1303271A
CN1303271A CN99806577A CN99806577A CN1303271A CN 1303271 A CN1303271 A CN 1303271A CN 99806577 A CN99806577 A CN 99806577A CN 99806577 A CN99806577 A CN 99806577A CN 1303271 A CN1303271 A CN 1303271A
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preparation
liposome
activating agent
carrier
antibacterial
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沃尔夫冈·弗莱舍
卡伦·赖默
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Euro Celtique SA
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
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    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
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    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

Use of an anti-inflammatory agent such as povidone iodine for the preparation of a pharmaceutical composition for the treatment of diseases of the lower respiratory tract which are susceptible to the administration of such agents.

Description

Be applied to the preparation of the antiinflammatory of lower respiratory tract, particularly antibacterial and/or promotion wound healing activating agent
The present invention relates to be applied to the antiinflammatory action that has of lower respiratory tract, particularly have antibiotic/or promote the preparation of the activating agent of wound healing characteristic.Described preparation is applied to trachea, bronchus and alveolar in the humans and animals lower respiratory tract especially.
In addition, the present invention relates to by using the method that a kind of pharmaceutical preparation prevented and treated infection.
Known a large amount of different antibiotics and antibacterial is used for the topical therapeutic infectious disease.The open defect of antibiotics activating agent is that bacterial infection shows preliminary toleration to these medicines and can obtain the toleration of moderate.In addition, antibiotics can cause patient's sensitization usually.The antibacterial that for example discharges halogen is also referred to as PVP-iodine such as betadin, and promptly poly-(1-vinyl-2-pyrrolidin-2-one)-iodine coordination compound can prevent toleration.Compare with antibiotics, antibacterial is seldom irritated.
At present, use the infectious disease of antibiotic therapy respiratory tract.Use the antibiotics activating agent through respiratory tract and become several summary of lower respiratory tract and research themes of paper of focusing on.For example, Ramsey etc. has described in 1999 the 340th volumes of " New England's medicine magazine " (" The New England Journal of Medicine ") the 1st phase 23-30 page or leaf and has periodically given to suck tobramycin to suffering from the cystic fibrosis patient.
Wiener-Kronish is at " antibiotic chemotherapy magazine " (" Journal of Antimicrobio1Chemotherapy ") (1996) 38, studied atomizing imipenum/cilastatin in the 809-818 page or leaf and has been used to the acute lung injury that prevents Rhodopseudomonas to bring out.
Schreier in several recent summaries for example at " medicinal application of liposome " (" Medicalapplications of liposomes "), Papahadjopoulos and Lasic (editor), Elsevier 1998) in described and resemble benzylpenicillin, tobramycin or A Kami star for the different antibiotics activating agent of pulmonary administration to be used for the treatment of infectious disease.
Yet, can cause complication known in those skilled in the art with antibiotic therapy.For example, suffer from the patient of acute or chronic bronchitis so that relief of symptoms with antibiotic therapy usually.This only can produce the toleration that causes the symptom antibacterial usually.Many respiratory tract diseases are caused by virus.Antibiotics and the infection that can not cure this class patient invalid to this class situation.
Agent of humans and animals externally used antimicrobial and/or promotion wound healing activating agent are disclosed among our the early stage patent EP 0 639 373.Especially, the Liposomal formulation of proof PVP-iodine can be locally applied to the eye outside in the document.These preparations generally adopt the dosage form of ointment, ointment, lotion, gelinite or drop.
Liposome be well-known pharmaceutical carrier and thus the liposome dosage form medicament be applied in the theme that has become research in the long duration.(" Pulmonarydelivery of liposomes ") (H.Schreier is at " controlled release magazine " (" Journal of ControlledRelease ") 24 for summary " pulmonary's transhipment of liposome ", the summary that relates to the medicine that uses pulmonary's transhipment liposomes enclose in the asthma therapies is provided 1993,209-223 page or leaf).In the document, proved the physical chemical characteristics of liposome aerosols and the treatment of respiratory tract has been used.The medicine that liposome carries out pulmonary transhipment that passes through after deliberation comprises for example anticarcinogen, peptide class, enzyme, antiasthmatics and antiallergic chemical compound and aforesaid antibiotics.Also (S.T.P. " pharmaceutical science " (Pharma.Sciences) 4 at " preparation and the vitro characteristics of liposome powdery aerosol " (" Formulation and in vitroperformance of liposome powder aerosols ") for H.Schreier, 1994,38-44 page or leaf) described liposome aerosols or used for example preparation of the liposome powder aerosol of Diskus in.
As can from the citation document viewed, although many attention are focused on liposome as on the pharmaceutical carrier, but seem also not relate in the prior art with liposome and the carrier of other granule as the activating agent of the antiinflammatory that is applied in the lower respiratory tract that particularly comprises trachea, bronchus and alveolar in the body, particularly antibacterial and/or promotion wound healing.
Above-mentioned of the prior art some relate to Liposomal formulation.Should understand the selectable pharmaceutical carrier with similar particle characteristics exists.These pharmaceutical carriers can often use and also use in description of the present invention to substitute liposome, and described pharmaceutical carrier comprises microsphere (generally comprising lipophilic polymer), nano-particle, " macropore granule " and for example drug substance molecule of parcel separately by using pulsed laser deposition (PLD) technology to make.These PLD methods can be used for the surface characteristic and the rate of release that are applied to lapping on the medicated powder and change various drug systems.
The content that relates to hereinafter it should be understood that and also can mix the selectable carrier of this class at liposome or particulate vector.
Known in the artly can realize to suck granule to respiratory tract administration by atomizing or spraying liposome, microsphere, macropore granule, PLD or nanoparticle formulations or by the dry powder that sucks corresponding preparations.
Except that may the emergency of the septicemia complication that threatens life, seeming that using disinfectant to body interior exists tangible obstacle in the art.
In general, even above-mentioned defective is arranged, antibiotic preparation seems it also is preferred.
An object of the present invention is to provide a kind of good Receptive antiinflammatory of easily using that has, particularly antibiotic and/or promote the preparation of wound healing, said preparation can make activating agent produce the release of prolongation and the local action of prolongation in lower respiratory tract.
According to the present invention, this purpose can reach, and promptly described preparation contains at least a antiinflammatory, particularly antibacterial and/or promotes the activating agent of wound healing in the particulate vector dosage form, as defined in the independent claims 1.
The present invention further comprises a kind of method for the treatment of the humans and animals lower respiratory tract, as defined in independent claims 21 and 22.
Dependent claims defines the other embodiment preferred of the present invention.
In description of the present invention, antiinflammatory is interpreted as the activating agent that comprises antibacterial as described below, antibiotics activating agent, corticosteroid and healing of wound.
In description of the present invention, with antibacterial be interpreted as comprise pharmaceutically acceptable and be suitable for treating to a certain extent lower respiratory tract can prepare their those disinfectant according to the present invention.
More particularly, antibacterial is particularly including the chemical compound of chemical compound that discharges oxygen and release halogen; Metallic compound such as silver and mercury compound; Organic disinfectant comprises alkyl and aryl phenol class and halogeno-benzene phenols, quinolines and acridine, hexahydropyrimidine class, quaternary ammonium compound and inferior amine salt and guanidine class particularly including chemical compound, alcohols, the phenol of release formaldehyde.
Promote the activating agent of wound healing to comprise that the promotion granulation takes place and epitheliogenic activating agent such as pantothenylol, allantoin class, azulenes hydro carbons, tannins and vitamin(e) B group chemical compound.
The present invention is according to the unexpected fact, be particularly liposome of particulate vector, the drug substance molecule that also comprises microsphere, nano-particle and parcel be suitable as very much be applied to lower respiratory tract antibacterial particularly betadin carrier and promote the carrier of the activating agent of wound healing.
Preparation of the present invention make to prolong discharges described one or more activating agents becomes possibility, and by produced on desired location with the interaction of cell surface prolong and Topically active.
On the other hand, the present invention is based on the further unexpected and beat all fact.Be well known in the art new systemic formation and can produce a difficult problem.Therefore, systemic reparation can be with the formation of scar tissue, and this can be deleterious on function and/or in the face-lifting or be unwanted at least.Hyperkeratosis and out-of-control hyperblastosis can cause severe impairment, thus cause dysfunction and also be certainly in the face-lifting institute unwanted.After infection and inflammation generation, regrowing and healing of tissue can produce vegetation and Symbiont.Therefore, well known in the art in the process of treatment disease, suitably the remodeling tissue is not only and is needed, and in fact also is necessary.
Find unexpectedly at present agent having ahtiphlogistic activity to be used separately or can obviously cause forming unwanted bodily tissue hardly with common the use in tissue repair and other tissue growth process of other this class activating agent.Therefore, not only in skin but also the scar tissue minimizing that in mucosa and other tissue such as muscle or internal's tissue, forms.Hyperkeratosis can be suppressed and Symbiont or also obviously minimizing of excrescent formation in the process of treatment infectious disease fully.
The purpose that the present invention reaches is relevant with the systemic reparation of improvement thus.The present invention has realized this purpose by using agent having ahtiphlogistic activity with the particulate vector dosage form defined in independent claims.
Be mounted with the particulate vector preparation of activating agent by atomizing, or the dry powder by sucking corresponding preparations can be to the preparation of respiratory tract administration antiinflammatory, antibiotic and/or healing of wound.For example, can prepare Liposomal formulation by make liposome be loaded with PVP iodine with common method.
Can also with the liposome that loads any with auxiliary substance such as low molecule saccharide, preferably lactose is pressed into the solid chemicals reserve that densification compresses together.Can or otherwise handle grinding of this medicament reserve or micronization then and obtain the granular pattern powder.For example, described in " the liposome aerosols inhalation is to the acute effect of healthy people volunteer's pulmonary function " (1991 the 99th volumes of Thomas etc. " preliminary report " (Preliminary report) 1268-1270 page or leaf), the Liposomal formulation of gained can be come administration by the mode of the said preparation of suction powder aerosol form.The pressure that is used to prepare the solid chemicals reserve that described densification compresses is preferably in the scope of 50-500MPa.This class medicament reserve is described among the WO94/14490 and doser is disclosed among the WO 93/24165.
The character of liposome or structure are generally not crucial.For example, can administration by inhalation aerosol such as EP 0 639 373 described in Liposomal formulation.The disclosure of EP 0 639 373 is introduced this description as a reference.
Preparation of the present invention obviously not only contains and is wrapped in particulate vector, and particularly the activating agent in the liposome resembles betadin.Seem to also have a certain amount of medicine that is not included in carrier inside.Preparation of the present invention shows tangible initial action usually, and this effect is except that activating agent is slow from carrier, prolongation is observed in addition discharging.This effect is observed in carrier comprises the situation of liposome especially.Although do not wish in conjunction with any theoretic explanation, imagination is except that being wrapped in the intravital activating agent of lipid at present, and some activating agent also is present in the outer surface that the outside and possible loosely of liposome is combined in liposome.This may be because active agent molecule combine what caused with liposome membrane maybe may be that active agent molecule because of formation one deck on surface of liposome causes, described layer segment or and even wrap up liposome fully in appearance.The type of this initial activity agent effect and amount can for example be subjected to the influence of selected concentration parameter.
Can use the general known amphiphilic substance that forms liposome membrane in the prior art in description of the present invention, condition is that they are pharmaceutically acceptable for required application.At present, the liposome formation system that contains lecithin is preferred.This type systematic can also contain hydrogenated soy phosphatidyl choline except that containing cholesterol and disodium succinate-hexahydrate; The particularly preferred hydrogenated soy phosphatidyl choline that is to use is as unique film former at present.
Described in the above-mentioned document and formed the known method of the prior art of liposome structure and generally they can be used for description of the present invention.Put it briefly, these methods comprise that mechanical agitation contains the suitable mixture of film forming matter and water or aqueous solution.Basically evenly preferably pass through suitable membrane filtration in the process of the liposome of size in formation.
The mean size of liposome of the present invention can change in the scope of broad, and general diameter is about the about 50 μ m of 1-, the preferred about 30 μ m of the about 1-of diameter range.For solution, less average diameter, for example diameter are about 100nm may be more suitable.
The uniform basically magnitude range that liposome of the present invention has is: the about 20 μ m-30 μ m of diameter range that are applied to trachea; Being applied to bronchial diameter range is about 10 μ m-20 μ m; And the diameter range that is applied to alveolar is about 1 μ m-6 μ m, particularly at 2-5 μ m.
If use another kind of particulate vector, their generally method preparations as known in the art so.Therefore, described in for example WO 95/15118, prepare the microsphere that is used to transport utmost point wide region therapeutic agent or enamel.
Can use nano-particle in some cases, condition be they can be loaded with capacity activating agent and can be according to the present invention to the lower respiratory tract administration.According to method as known in the art, as for example Heyder (GSF Munchen) " being transported to the medicine of pulmonary " (" Drugs delivered to thelung "-, Abstracts IV, Hilton Head Island Conference, in May, 1998) can prepare them described in.
In short non-water law, use pulsed laser deposition (PLD) instrument and polymerization target thing that the method that integument is applied to medicated powder also is suitable for forming granular preparation of the present invention.For example, Talton etc. have described these methods in " being used to improve the novel pack of dry method transhipment " (" Novel Coating Method for Improved DryDelivery ", Univ.of Florida UF 1887 (1998)).
Suitable in addition movement system has been used as David A.Edwards etc. at the disclosed macropore granule of " the macropore granule that is used for the pulmonary drug transhipment " (" science " (Science) 20 days the 276th June in 1997 volume 1868-1871 page or leaf).For example, being applied to the macropore particle diameter of the present invention of alveolar can be in the scope of about 5-20 μ m.
Preferred agent having ahtiphlogistic activity comprises the activating agent of antibacterial, antibiotics, corticosteroid and promotion wound healing, they can be used or the use that is bonded to each other as one matter.
Preferred antibacterial comprise well-knownly produce snap action, have broad spectrum of activity, the drug substance of low general toxicity and the favorable tissue compatibility.For example, they can be selected from following material group: metallic compound, phenolic compound, detergent, iodine and iodine coordination compound.Particularly preferred antibacterial is a betadin.
The preferred activating agent of wound healing that promotes comprises the material of having described in the application's document.Preferred this class activating agent comprises the known epitheliogenic material that is used to promote.These materials comprise vitamin, particularly from the vitamin of vitamin B complex; Allantoin; Some glycosides Portugal cyclic hydrocar-bons etc.
Some present highly preferred embodiment of the present invention is included in tissue repair, particularly about the compositions of the agent having ahtiphlogistic activity or this class activating agent that show advantageous effect in function and the face-lifting tissue remodelling.In these embodiments, activating agent normally antibacterial such as PVP-iodine or antibiotics.
In preferred embodiments, contain antiinflammatory, particularly the preparation of the present invention of antibacterial and/or promotion wound healing activating agent can further contain such as the such activating agent of anesthetis.Preparation of the present invention can also contain reagent commonly used in addition and comprise that the reagent of adjuvant and additive, antioxidant, preservative agent or formation denseness is such as viscosity adjustment additive, emulsifying agent etc.
In general, select concentration, the granular size of preparation, bearing capacity of activating agent etc. so that meet the parameter about Liposomal formulation described herein basically according to the selectable carrier of this class.This class of selecting and providing is gratifying in being engaged in those of ordinary skill in the art based on the parameter of clearly experiment especially.
The application very preferably of Liposomal formulation of the present invention at present is to use it for the infection that the treatment lower respiratory tract comprises trachea, bronchus and alveolar, particularly when described Liposomal formulation contains betadin.In addition, in this indication, antibiotic preparation of the present invention, particularly those preparations that contain PVP iodine have not tolerific major advantage and can cause very low anaphylaxis; Make that simultaneously the expense of therapy with wide spectrum effect is very cheap.For example, betadin Liposomal formulation of the present invention antiviral effectively.In addition, the Liposomal formulation of antibacterial such as betadin can make described activating agent for example prolong the liposome of alveolar region and discharge from activating agent being transported to lung areas.Compare with the antiseptic solution preparation of routine, this will make antibiotic substance produce the prolongation effect and not need thus frequently to use.
The present invention also is used for the treatment of infectious disease or is used to alleviate such as the such disease with opportunistic infection of HIV infection.Can also treat the patient who has the immunosuppressant system after for example organ transplantation according to the present invention.Especially, can be with betadin preparation for treating of the present invention acute or chronic bronchitis, pneumonia, bronchiectasis, cystic fibrosis, diphtheria, tuberculosis.
In addition, purposes very preferably is a tissue repair, particularly the remodeling of function and face-lifting tissue.
Preparation of the present invention can adopt different dosage forms, and these dosage forms are suitable for through the lower respiratory tract administration, comprises being suitable for producing sucking particulate pharmaceutically acceptable solid or liquid preparation.Therefore, preparation of the present invention can be the reserve form of (powder) aerosol dosage forms or compact solid medicament, preferred ring-type tablet, more preferably contains capsule, powder, spray, Emulsion, dispersion liquid, suspensoid and even the solution of described carrier and one or more activating agents.
In general, on the one hand, the amount of activating agent is determined according to required being used in the preparation of the present invention; And on the other hand, determine according to the capacity that carries of the carrier formulation that is used for described activating agent.
For making preparation of the present invention carry the activating agent of a large amount of activating agents or high dose, for powder or preferred atomization preparation of powder aerosol or aerosol.Put it briefly, the amount of activating agent can be in the lower bound of described activating agent effectiveness to the concentration range between the maximum bearing capacity of described activating agent in the respective carrier preparation in the carrier formulation of the present invention.
More particularly, such as betadin, carrier formulation of the present invention especially carrier is that solution or dispersion liquid can contain the 0.1-10g activating agent in the preparation of liposome in the 100g preparation for antibacterial.This class preparation generally contains the liposome film forming matter, particularly lecithin of 1-5g in every 100g preparation.
Aerosol of the present invention or spray contain the liposomal active agent preparation that reaches 50mg usually, reach and are higher than 100mg liposomal active agent preparation and for example can contain the liposomal active agent preparation of 20mg by 5 spraying dosed administrations at every turn and can contain.
Described preparation generally contains 10%wt at least in the liposome (or another kind of carrier granular) of carrying activating agent reaches 50wt.-% and even the above activating agent of 50wt.-% such as PVP-iodine and can contain.If activating agent is a PVP-iodine, can utilize the consumption of iodine generally to be about 10wt.-% (is benchmark with PVP-iodine) so.
More specifically preparation from embodiment merits attention.
The features and advantages of the present invention can be more remarkable from the description of preferred embodiment subsequently.Comprise in the embodiment of preferred forms that at these betadin is that typical antibacterial and selection liposome are carrier.Yet, although this class preparation is particularly preferred, this should not limit the invention in antibacterial or the antibacterial betadin and/or as the liposome of carrier.
A kind of method for optimizing of preparation liposome of the present invention is generally as described below:
With the lipid film forming component for example lecithin be dissolved in 2: 1 mixture of suitable solvent such as chloroform or methanol and chloroform and under aseptic condition, filter.Then, the evaporation by the control solvent makes the lipid thin film produce on such as bead in highly aseptic surface matrix.In some cases, can need not special substrate increase surface area being used for being enough to form thin film on the inner surface of container of evaporating solvent.
The activating agent of being sneaked in the described Liposomal formulation by electrolyte ingredient and (one or more) prepares aqueous system.This class aqueous system for example can contain the 10mmol/l dibastic sodium phosphate and 0.9% sodium chloride, pH are 7.4; This aqueous system also contains the activating agent of aequum at least, and in an embodiment, this activating agent is a betadin.Described aqueous system contains one or more excessive activating agents usually.
Generally can form liposome by under the situation that the described thin film existence that is formed by lipid component is arranged, stirring described aqueous system.In this stage, can add other additive so that improve Liposomal formulation; For example, can add sodium cholate.By mechanism such as by for example polycarbonate membrane pressure filtration or the centrifugal formation that also can influence liposome.In general, the electrolyte solution that for example uses with the solution for preparing above-mentioned activating agent washs thick Liposomal dispersion.
When obtaining to have the liposome of required size distribution and having carried out washing, they can be dispersed in the aforesaid electrolyte solution again, described electrolyte solution also contains saccharide such as sucrose or suitable sugar replacement usually.Also can be with described dispersion liquid lyophilizing with its lyophilization.Before use, can carry out suitable mechanical agitation and make lyophilized products dissolve (reconstitute) again by adding entry and under the transition temperature of lipid component, for example being 55 ℃ for hydrogenated soy phosphatidyl choline.
In the following example, use hydrogenated soy phosphatidyl choline available from German Lukas Meyer (EPIKURON (TM) 200SH or available from PHOSPHOLIPON (TM) 90H of German Nattermann Phospholipid GmbH.But, also can use acceptable liposome film forming matter on the other medicines and those skilled in the art can find easily according to selecting suitable another kind of liposome formation system described in the prior art.
The embodiment I
At 1000ml the glass flask of the bead that is used for increasing surface area is housed, 51.9mg cholesterol and 213mg hydrogenated soy phosphatidyl choline is dissolved in the mixture by the methanol of 2: 1 mixed and chloroform of capacity.Evaporating solvent in a vacuum then is up to till forming thin film on the flask inner surface and on the bead.
2.4gPVP iodine (contain have an appointment 10% utilized iodine) is dissolved in separately in the 12ml water.
In addition, in independent container, with 8.77g sodium chloride and 1.78g Na 2HPO 42H 2O is dissolved in 400ml water.Again water is added to the cumulative volume of 980ml, and adds about 12ml 1N hydrochloric acid then so that with pH regulator to 7.4.Then water adds to accurate 1000ml with this solution.
In the 4th container, 900mg sucrose and 57mg disodium succinate are dissolved in 12ml water.
Then above-mentioned PVP iodine solution is joined on the lipid thin film in the above-mentioned flask and with the mixture jolting till the Film Fractionation.From flask, isolate the Liposomal formulation of generation in the hydration lipid.Product is centrifugal and supernatant discarded.Sucrose solution is added to 12ml and once more that product is centrifugal.After this abandoning supernatant once more.In this stage, use sucrose solution or sodium chloride buffer solution to carry out further washing step.
After last centrifugation step and abandoning supernatant, add 12ml sodium chloride buffer solution and make the liposome uniform distribution therein.Then the product branch is packed in the phial that the 2ml Liposomal dispersion is housed separately and phial is carried out step of freeze drying.
After the lyophilizing, contain the 40mg solid of having an appointment in each phial.
The less defective that embodiment I method has is that used PVP iodine solution has suitable viscosity and more is difficult to processing thus because of solid percentage ratio is high.
The embodiment II
At 2000ml the flask of the bead that is used for increasing surface area is housed, 173mg hydrogenated soy phosphatidyl choline and 90mg disodium succinate are dissolved in the mixture of about 60ml methanol/chloroform by 2: 1 mixed.Remove in a vacuum and desolvate, till forming thin film.
4g PVP iodine (10% can utilize iodine) is dissolved in the sodium chloride buffer solution described in the 40ml embodiment I and joins on the lipid thin film in the described flask.The flask jolting is arrived till Film Fractionation and the liposome formation then.
Centrifugal and the abandoning supernatant with product.
In consequent liposome precipitation, add 40ml sodium chloride buffer solution again and repeat centrifugation step.Abandoning supernatant once more.In this stage, if necessary, can the repeated washing step.
After last centrifugal and decantation steps, once more 40ml sodium chloride buffer solution is joined in the sedimentary liposome.Then uniform dispersion liquid branch is packed in the phial that about 2ml Liposomal dispersion is housed separately and phial is carried out step of freeze drying.This step makes the lyophilized solid that produces about 200mg in each phial.
Be similar to the embodiment I, use hydration step and purpose to be to comprise rate under the situation that said method is having organic solvent to exist after thin film forms and be 5-15%.These methods are general to produce quite big itself and normally multiwalled liposome.
Thick liposome form the back or behind any washing step subsequently by through the high-pressure filteration step of suitable film such as polycarbonate membrane or directly by using high pressure homogenize method can improve said method.This step produces the littler unilamellar liposome of the amount increase of institute's coating active agent.
Can use the known method that produces other prior art of less evenly big small liposome to substitute high pressure homogenize method.
The embodiment III
Containing the betadin liposome of lyophilizing (leophilised) material that obtains according to above-mentioned general preparation method and 20mg lactose by 20g prepares to be suitable for producing and can suck particulate capsule by being forced into 500MPa.By polishing, use powder inhalator (by the Orbital-Inhaler of Brin Tech International Ltd. generation) to produce powder or powder aerosol by the hard capsule that obtains.
Can also prepare the exemplary formulations that is similar to above-mentioned preparation, said preparation contains the activating agent that can promote wound healing rather than and does not comprise that antibacterial is such as for example disclosed in the above-described embodiments betadin.Yet, preferred at present activating agent (if certainly) and the antibacterial that promotes wound healing that use.
In order to use the invention preparation to patient, can use system known per such as inhaler, powder inhalator, two chambers air pressure medicated bag, aerosol spray allotter, aerosol apparatus, compressor etc.
The embodiment IV
By the pneumatic nebulizer Liposomal formulation that atomizes.The output of use aerosol generation and the aerosol feature of liposome have been described in advance.Total average pneumatic diameter that the droplet that is produced has is about 2.4 μ m and is thus suitable for depositing in alveolar region.
Use the invention preparation to carry out efficacy test then, as follows:
The test I
This is the in vitro tests by the bactericidal action of betadin Liposomal formulation generation of the present invention.This test is based on the quantitative suspension test described in " Richtlinien der Deutschen Gesellschft fur Hygiene undMikrobiologie " (1989).In this test, antibacterial is used to kill the main difficult problem of staphylococcus aureus (ATCC 29213), a hospital health aspect.
Used Liposomal formulation is a Liposomal formulation used in the embodiment I.Different times of contact between 1-120 minute, mensuration can be killed the least concentration of the preparation aqueous solution of staphylococcus bacteria.
The result is as shown in table 1.
Table 1
Time of contact (minute) bacteriocidal concentration
1,2,3,4 ≥0.060％
5,30,60 ≥0.015％
120 ≥0.007％
The result shows at short (1-4 minute) bacteriocidal concentration time of contact low to 0.06%; And longer time of contact (120 minutes) bacteriocidal concentration can hang down to 0.007%.
The test II
Wutzler etc. after deliberation liposome PVP-iodine killing the virus and kill chlamydia activity (learning and the meeting material that catches) in cell culture referring to the 9th clinical microbe of europe of holding in Berlin in March, 1999.In cell culture, liposome PVP-iodine is very effective to herpes simplex 1 type virus and 8 type adenoviruss, and secular warp is tested the acceptability that the cytotoxicity experiment of cell line shows the liposome dosage form in a large number and is better than moisture PVP-iodine.The liposome dosage form of PVP-iodine is non-genotoxicity.
The test III
PVP-iodine hydrogel Liposomal formulation with 3% and 3% PVP-iodine Ointment agent compare, and wherein activating agent is not the liposome dosage form.The external standardization culture that activating agent is applied to rat skin and peritoneum explant is used to screen the histocompatibility of the anti-infective of skin and wound.
At the rate of growth that exposed 30 minutes and cultivated the explant of back institute cultivation with test substances.
In addition, according to peritoneum rate of growth and skin growth rate, in the result, clearly proved the acceptable preferably basically of Liposomal formulation.
Use the peritoneum rate of growth of ointment to reach 85%, and the rate of growth of skin reach 90%; Using the peritoneum rate of growth of liposome aqueogel is 96%, and the skin growth rate is 108%; These numerical value are compared as 100% numerical value in the controlled trial of activating agent with using Ringer's solution.

Claims (43)

1. a method that is used to prepare the pharmaceutical preparation of antibacterial that is applied to lower respiratory tract and/or the activating agent that promotes wound healing is characterized in that described preparation contains at least a described activating agent and particulate vector.
2. the method for claim 1 is characterized in that described particulate vector comprises at least a in the molecule of liposome, microsphere, nano-particle, macropore granule or laser pulse polymer parcel.
3. method according to claim 1 and 2 is characterized in that the described activating agent of largest portion is wrapped in described carrier inside at least, particularly in the inside of liposome or microsphere carrier.
4. according to any one described method among the claim 1-3, it is characterized in that described antibacterial is selected from chemical compound that discharges oxygen and the chemical compound that discharges halogen; Metallic compound such as silver and mercury compound; Organic disinfectant comprises alkyl and aryl phenol class and halogeno-benzene phenols, quinolines and acridine, hexahydropyrimidine class, quaternary ammonium compound and inferior amine salt and guanidine class particularly including chemical compound, alcohols, the phenol of release formaldehyde.
5. method according to claim 4, it is characterized in that described antibacterial is selected from following material group: metallic compound is such as mercury compound; Phenol derivatives such as thymol, acetaminol and Perchlorobenzene; Iodine and iodine coordination compound.
6. method according to claim 5 is characterized in that described antibacterial is a betadin.
7. according to any one described method among the claim 1-6, the activating agent that it is characterized in that described promotion wound healing be selected from promote granulation to take place and epitheliogenic activating agent such as pantothenylol, allantoin class, azulenes hydro carbons, tannins, from the chemical compound of vitamin B series or the activating agent of a similar effect.
8. any one described method in requiring according to aforesaid right is characterized in that described preparation contains the activating agent of at least a antibacterial and at least a promotion wound healing.
9. any one described method in requiring according to aforesaid right is characterized in that the big or small uniformly basically scope that described carrier granular, particularly liposome have is the about 50 μ m of about 1-; The about 30 μ m of the about 1-of preferable range.
10. method according to claim 9 is characterized in that the scope of uniform diameter basically that described carrier granular, particularly liposome have is: the about 20 μ m-30 μ m of diameter that are applied to trachea; Be applied to the about 10 μ m-20 μ m of bronchial diameter; And the about 1 μ m-6 μ m of the diameter that is applied to alveolar, particularly at 2-5 μ m.
11., it is characterized in that described carrier formulation, particularly Liposomal formulation can preferably discharge described activating agent in the time bar that prolongs in time limit time expand of several hours persistent period according to any one described method in the aforesaid right requirement.
12. method according to claim 11 is characterized in that described carrier formulation, particularly Liposomal formulation can discharge described activating agent with about identical rate of release in time limit release time.
13., it is characterized in that described preparation also contains at least a narcotic activity agent according to any one described method in the aforesaid right requirement.
14., it is characterized in that described preparation contains the additive of additive and adjuvant such as preservative agent, antioxidant and formation denseness according to any one described method in the aforesaid right requirement.
15. according to any one described method among the claim 1-14, described preparation is to be used for through containing of lower respiratory tract administration described activating agent and the dosage forms, particularly liposome dosage form of carrier, preferred aerosol dosage forms, especially powder aerosol dosage form.
16. according to any one described method among the claim 1-14, described preparation is the reserve form of compact solid medicament, preferred ring-type tablet, more preferably contain capsule, powder, spray, Emulsion, dispersion liquid, suspension emulsion or the solution of described carrier and one or more activating agents in pharmaceutically acceptable solid or liquid preparation, they are suitable for producing the granule that can suck.
17. according to any one described method in the aforesaid right requirement, described preparation is the dosage forms that is used for through the lower respiratory tract administration, it comprises:
A) contain the liposome of pharmaceutically acceptable liposome film forming matter; With
B) 0.1-2%PVP iodine solution (nearly 10% utilized iodine in PVP iodine coordination compound), major part is at least wherein wrapped up by described liposome membrane;
Wherein said liposome basically uniformly size be about additive, adjuvant and the auxiliary substance that the about 50 μ m of 1-and described in this case preparation also contain conventional pharmaceutical preparation.
18. method according to claim 17 is characterized in that the scope of uniform diameter basically that described liposome has is: the about 20 μ m-30 μ m of diameter that are applied to trachea; Be applied to the about 10 μ m-20 μ m of bronchial diameter; And the about 1 μ m-6 μ m of the diameter that is applied to alveolar, preferred about 2 μ m-5 μ m.
19. according to any one described method among the claim 1-18, wherein said preparation is suitable for treating infectious disease or alleviates such as HIV and infects such disease with opportunistic infection or immunosuppressant system.
20. according to any one described method among the claim 1-18, wherein said preparation is suitable for treating acute or chronic bronchitis, pneumonia, bronchiectasis, cystic fibrosis, diphtheria and/or tuberculosis.
21. according to any one described method among the claim 1-20, wherein said preparation is suitable for the remodeling and the repairing and treating of function and face-lifting tissue.
22. method of preventing or treating human or animal's lower respiratory infection, this method contains at least a antibacterial and/or promotes the pharmaceutical preparation of the activating agent of wound healing to carry out by using for described respiratory tract, mixes with particulate vector at the activating agent described in the described preparation.
23. method of in the lower respiratory tract of humans and animals, carrying out function and face-lifting tissue remodelling and reparation, this method contains at least a antiinflammatory, particularly antibacterial and/or promotes the activating agent of wound healing and the pharmaceutical preparation of particulate vector to carry out by using for described respiratory tract.
24. the method for claim 22 or 23, wherein said carrier comprise at least a in the molecule of liposome, microsphere, nano-particle, macropore granule or laser pulse polymer parcel.
25. the method for claim 22 or 23, wherein the described activating agent of largest portion is wrapped in described carrier inside at least, particularly in the inside of liposome or microsphere carrier.
26. the method for claim 23, wherein said antiinflammatory are selected from the activating agent of antibacterial, antibiotics, corticosteroid and promotion wound healing.
27. the method for claim 22 or 23, wherein said antibacterial are selected from chemical compound that discharges oxygen and the chemical compound that discharges halogen; Metallic compound such as silver and mercury compound; Organic disinfectant comprises alkyl and aryl phenol class and halogeno-benzene phenols, quinolines and acridine, hexahydropyrimidine class, quaternary ammonium compound and inferior amine salt and guanidine class particularly including chemical compound, alcohols, the phenol of release formaldehyde.
28. the method for claim 22 or 23, wherein said antibacterial are selected from following material group: metallic compound is such as mercury compound; Phenol derivatives such as thymol, acetaminol and Perchlorobenzene; Iodine and iodine coordination compound.
29. the method for claim 22 or 23, wherein said antibacterial is a betadin.
30. the method for claim 22 or 23, the activating agent of wherein said promotion wound healing be selected from promote granulation to take place and epitheliogenic activating agent such as pantothenylol, allantoin class, azulenes hydro carbons, tannins, from the chemical compound of vitamin B series or the activating agent of a similar effect.
31. the method for claim 22 or 23, wherein said preparation contains the activating agent of at least a antibacterial and at least a promotion wound healing.
32. the big or small uniformly basically scope that the method for claim 22 or 23, wherein said carrier granular, particularly liposome have is the about 50 μ m of about 1-; The about 30 μ m of the about 1-of preferable range.
33. the scope of uniform diameter basically that the method for claim 32, wherein said carrier granular, particularly liposome have is: the about 20 μ m-30 μ m of diameter that are applied to trachea; Be applied to the about 10 μ m-20 μ m of bronchial diameter; And the about 1 μ m-6 μ m of the diameter that is applied to alveolar, particularly at 2-5 μ m.
34. the method for claim 22 or 23, wherein said carrier formulation, particularly Liposomal formulation can preferably discharge described activating agent in time limit time expand of several hours persistent period in the time bar that prolongs.
35. the method for claim 22 or 23, wherein said carrier formulation, particularly Liposomal formulation can discharge described activating agent with about identical rate of release in time limit release time.
36. the method for claim 22 or 23, wherein said preparation also contain at least a narcotic activity agent.
37. the method for claim 22 or 23, wherein said preparation contain the additive of additive and adjuvant such as preservative agent, antioxidant and formation denseness.
38. the method for claim 22 or 23, described preparation are to be used for through containing of lower respiratory tract administration described activating agent and the dosage forms, particularly liposome dosage form of carrier, preferred aerosol dosage forms, especially powder aerosol dosage form.
39. the method for claim 22 or 23, described preparation is the savings thing form of compact solid medicament, preferred ring-type tablet, more preferably contain capsule, powder, spray, Emulsion, dispersion liquid, suspensoid or the solution of described carrier and one or more activating agents in pharmaceutically acceptable solid or liquid preparation, they are suitable for producing the granule that can suck.
40. the method for claim 22 or 23, described preparation is the dosage forms that is used for through the lower respiratory tract administration, and it comprises:
A) contain the liposome of pharmaceutically acceptable liposome film forming matter; With
B) 0.1-2%PVP iodine solution (nearly 10% utilized iodine in PVP iodine coordination compound), major part is at least wherein wrapped up by described liposome membrane;
Wherein said liposome basically uniformly size be about additive, adjuvant and the auxiliary substance that the about 50 μ m of 1-and described in this case preparation also contain conventional pharmaceutical preparation.
41. the scope of uniform diameter basically that the method for claim 22 or 23, wherein said liposome have is: the about 20 μ m-30 μ m of diameter that are applied to trachea; Be applied to the about 10 μ m-20 μ m of bronchial diameter; And the about 1 μ m-6 μ m of the diameter that is applied to alveolar, preferred about 2 μ m-5 μ m.
42. being suitable for treating infectious disease or alleviating such as HIV, the method for claim 22 alive 23, wherein said preparation infect such disease with opportunistic infection or immunosuppressant system.
43. the method for claim 22 or 23, wherein said preparation are suitable for treating acute or chronic bronchitis, pneumonia, bronchiectasis, cystic fibrosis, diphtheria and/or tuberculosis.
CN99806577A 1998-05-27 1999-05-27 Preparations for application of anti-inflammatory, especially antiseptic agents and/or agents promoting healing of wounds, to lower respiratory tract Pending CN1303271A (en)

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CN108743537B (en) * 2012-05-21 2021-06-11 英斯麦德公司 System for treating pulmonary infections
CN110799179A (en) * 2017-07-04 2020-02-14 富陆凯米有限责任公司 Solid composition comprising iodine reagent and sodium chloride with improved water solubility and antiviral and antibacterial composition for eye, oral cavity, nasal cavity or inhalation comprising aqueous solution thereof

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